Breast cancer is the second leading cause of cancer deaths in women and is the most common cancer among women. The primary cause of death in breast cancer is metastasis, a process that is still poorly understood, and it is still not possible to accurately predict the risk of metastasis formation in patients. The specification of cell fate occurs through the establishment of hierarchical networks of transcription factors. We have identified GATA-3 in a genome-wide microarray screen as being the most highly expressed transcription factor in the mammary epithelium of pubertal mice and have shown that GATA-3 plays a fundamental role in the maintenance of the luminal cell fate in the adult mammary gland. We hypothesize that GATA-3 may be playing a causal role in the pathogenesis of breast cancer. Indeed in human breast cancer GATA-3 loss is an indicator of poor prognosis. In mouse, well differentiated tumors with high GATA- 3 expression have a low propensity for metastasis, whereas poorly differentiated tumors with low GATA-3 expression have a greater propensity for metastasis. We postulate that GATA-3 maintains the differentiation of breast neoplasms, and its loss plays a causal role in malignant progression: During neoplastic progression, GATA-3 maintains luminal differentiation and suppresses tumor cell proliferation, the recruitment of inflammatory cells and tumor vasculature, the onset of tumor cell dissemination and the acquisition of metastatic capability. We will use mammary tumor prone transgenic mice to study cancer growth and metastasis and examine the relationship between GATA-3 loss and tumor progression, including mounting an inflammatory response, angiogenesis and tumor cell dissemination. By removing GATA-3 or altering its potential downstream effectors we expect to increase metastasis. By re-expressing GATA-3 we hope to revert the phenotype to one with a better prognosis. Regulating the expression of these master regulatory genes may represent an important drug target for prevention and cure of breast cancer. With more than 1.2 million women diagnosed this year worldwide, these studies have the potential of providing better diagnosis, more accurate predicting of poor prognosis and open the potential for new therapies. If we could prevent the loss of GATA-3 or reactivate it in metastasizing tumors we would greatly improve breast cancer outcome and save the lives of millions of women. PUBLIC HEALTH RELEVANCE: Breast cancer is the second leading cause of cancer deaths in women and is the most common cancer among women. This study addresses an important aspect of women's health, that of how GATA-3 regulates the differentiated state of breast tumors and prevents malignant conversion. If we could prevent the loss of GATA-3 or reactivate it in metastasizing tumors we would greatly improve breast cancer outcome and save the lives of millions of women. These studies may form the basis of intervention and therapy in breast cancer, potentially preventing premalignant lesions from becoming malignant and metastasizing.